Induction of apoptosis of human primary osteoclasts treated with extracts from the medicinal plant Emblica officinalis

<p>Abstract</p> <p>Background</p> <p>Osteoclasts (OCs) are involved in rheumatoid arthritis and in several pathologies associated with bone loss. Recent results support the concept that some medicinal plants and derived natural products are of great interest for developing therapeutic strategies against bone disorders, including rheumatoid arthritis and osteoporosis. In this study we determined whether extracts of <it>Emblica officinalis </it>fruits display activity of possible interest for the treatment of rheumatoid arthritis and osteoporosis by activating programmed cell death of human primary osteoclasts.</p> <p>Methods</p> <p>The effects of extracts from <it>Emblica officinalis </it>on differentiation and survival of human primary OCs cultures obtained from peripheral blood were determined by tartrate-acid resistant acid phosphatase (TRAP)-positivity and colorimetric MTT assay. The effects of <it>Emblica officinalis </it>extracts on induction of OCs apoptosis were studied using TUNEL and immunocytochemical analysis of FAS receptor expression. Finally, <it>in vitro </it>effects of <it>Emblica officinalis </it>extracts on NF-kB transcription factor activity were determined by gel shift experiments.</p> <p>Results</p> <p>Extracts of <it>Emblica officinalis </it>were able to induce programmed cell death of mature OCs, without altering, at the concentrations employed in our study, the process of osteoclastogenesis. <it>Emblica officinalis </it>increased the expression levels of Fas, a critical member of the apoptotic pathway. Gel shift experiments demonstrated that <it>Emblica officinalis </it>extracts act by interfering with NF-kB activity, a transcription factor involved in osteoclast biology. The data obtained demonstrate that <it>Emblica officinalis </it>extracts selectively compete with the binding of transcription factor NF-kB to its specific target DNA sequences. This effect might explain the observed effects of <it>Emblica officinalis </it>on the expression levels of interleukin-6, a NF-kB specific target gene.</p> <p>Conclusion</p> <p>Induction of apoptosis of osteoclasts could be an important strategy both in interfering with rheumatoid arthritis complications of the bone skeleton leading to joint destruction, and preventing and reducing osteoporosis. Accordingly, we suggest the application of <it>Emblica officinalis </it>extracts as an alternative tool for therapy applied to bone diseases.</p

Climatic risks and impacts in South Asia: extremes of water scarcity and excess

This paper reviews the current knowledge of climatic risks and impacts in South Asia associated with anthropogenic warming levels of 1.5°C to 4°C above pre-industrial values in the 21st century. It is based on the World Bank Report “Turn Down the Heat, Climate Extremes, Regional Impacts and the Case for Resilience” (2013). Many of the climate change impacts in the region, which appear quite severe even with relatively modest warming of 1.5–2°C, pose significant hazards to development. For example, increased monsoon variability and loss or glacial meltwater will likely confront populations with ongoing and multiple challenges. The result is a significant risk to stable and reliable water resources for the region, with increases in peak flows potentially causing floods and dry season flow reductions threatening agriculture. Irrespective of the anticipated economic development and growth, climate projections indicate that large parts of South Asia’s growing population and especially the poor are likely to remain highly vulnerable to climate change

Inhibitory effects of medicinal plant extracts on interactions between DNA and transcription factors involved in inflammation

Alteration of gene expression is one of the approaches to control the expression of selected genes and could be achieved by molecules acting on the interactions between transcription factors and DNA. In this respect, DNA-binding drugs are of great interest and object of a large number of research articles. The most suitable techniques for a fast screening are the electrophoretic mobility shift assay and the filter binding approach. In this communication, we present evidence showing the ability to inhibit the interactions between nuclear factors and the specific DNA elements. Among the results obtained, we found low concentrations of Emblica officinalis, Vernonia anthelmintica, Terminalia arjuna and Rumex maritimus, and very low concentrations of Saraca asoka extracts inhibit NF-kB-DNA interactions. On the contrary, high amounts of extracts from Argemone mexican were still unable to inhibit NF-kB/DNA interactions. The employment of several analytical and preparative procedures, among which preparative and analytic high-performance liquid chromatography (HPLC), liquid- chromatography/mass-spectrometry (LC/MS) and gas-chromatography/mass-spectrometry (GC/MS), will help in identifying the bioactive compounds responsible for this very interesting feature

Ligand-based computer-aided discovery of tyrosinase inhibitors. Applications of the TOMOCOMD-CARDD method to the elucidation of new compounds

In this review an overview of the application of computational approaches is given. Specifically, the uses of Quantitative Structure-Activity Relationship (QSAR) methods for in silico identification of new families of compounds as novel tyrosinase inhibitors are revised. Assembling, validation of models through prediction series, and virtual screening of external data sets are also shown, to prove the accuracy of the QSAR models obtained with the TOMOCOMD-CARDD (TOpological MOlecular COMputational Design Computer-Aided Rational Drug Design) software and Linear Discriminant Analysis (LDA) as statistical technique. Together with this, a database is collected for these QSAR studies, and could be considered a useful tool in future QSAR modeling of tyrosinase activity and for scientists that work in the field of this enzyme and its inhibitors. Finally, a translation to real world applications is shown by the use of QSAR models in the identification and posterior in-vitro evaluation of different families of compounds. Several different classes of compounds from various sources (natural and synthetic) were identified. Between them, we can find tetraketones, cycloartanes, ethylsteroids, lignans, dicoumarins and vanilloid derivatives. Finally, some considerations are discussed in order to improve the identification of novel drug-like compounds based on the use of QSAR-Ligand-Based Virtual Screening (LBVS

A rational workflow for sequential virtual screening of chemical libraries on searching for new tyrosinase inhibitors

The tyrosinase is a bifunctional, copper-containing enzyme widely distributed in the phylogenetic tree. This enzyme is involved in the production of melanin and some other pigments in humans, animals and plants, including skin pigmentations in mammals, and browning process in plants and vegetables. Therefore, enzyme inhibitors has been under the attention of the scientist community, due to its broad applications in food, cosmetic, agricultural and medicinal fields, to avoid the undesirable effects of abnormal melanin overproduction. However, the research of novel chemical with antityrosinase activity demands the use of more efficient tools to speed up the tyrosinase inhibitors discovery process. This chapter is focused in the different components of a predictive modeling workflow for the identification and prioritization of potential new compounds with activity against the tyrosinase enzyme. In this case, two structure chemical libraries Spectrum Collection and Drugbank are used in this attempt to combine different virtual screening data mining techniques, in a sequential manner helping to avoid the usually expensive and time consuming traditional methods. Some of the sequential steps summarize here comprise the use of drug-likeness filters, similarity searching, classification and potency QSAR multiclassifier systems, modeling molecular interactions systems, and similarity/diversity analysis. Finally, the methodologies showed here provide a rational workflow for virtual screening hit analysis and selection as a promissory drug discovery strategy for use in target identification phase

Tyrosinase enzyme: 2. Inhibitors from natural and synthetic origins = La enzima tirosinasa: 2. Inhibidores de origen natural y sintético

In this work there are tackled in a general way the tyrosinase inhibitor compounds, the limiting enzyme and the fundamental key for the skin pigmentation control in human beings. The main characteristics of the depigmenting agents used in the medical practice are depicted. Besides, the compounds studied until nowadays are showed, which are grouped taking into account its origin: naturals, synthetics and drug with other therapeutic uses, discovered with inhibitory activity against the enzyme. Finally the last advances in the cheminformatic and molecular modeling field related with the study of the enzyme and its inhibitors are discussed

QSAR-Based CMs and TOMOCOMD-CARD Approach for the Discovery of New Tyrosinase Inhibitor Chemicals.

Tyrosinase is an oxidoreductase enzyme (EC 1.14.18.1) involved in the two main steps of the biochemical melanin pathway. In humans it is also related to the process of freeradical scavenging avoiding UV-radiations side-effects. However, abnormal overproduction of melanin lead to hyperpigmentation, that includes, melanoma, lentigenes, age spots and other skin disorders. Therefore, the research of novel chemical with inhibitory activity against the enzyme remains as a challenge to scientific community. In this chapter we survey the results achieved in the elucidation of new tyrosinase inhibitors by using Quantitative Structure-Activity Relationships (QSAR) and TOMOCOMD-CARDD (TOpological MOlecular COMputational Design-Computer-Aided Rational Drug Design) approach. Later, the use of different chemometric, machine learning and artificial intelligence techniques for modeling the tyrosinase inhibitory activity is showed. Finally, it has been shown that the algorithm proposed in this chapter was being used to the ligand-based virtual screening of several in-house databases, and many classes of compounds from both natural and synthetic sources. These compounds were found to have potent inhibitory profiles against the enzyme compared to the current reference depigmenting agents, kojic acid and L-mimosine